OATP1B1 Inhibitor Drugs Requiring Reduced Eluxadoline Dose
When prescribing eluxadoline, reduce the dose to 75 mg twice daily in patients receiving concomitant OATP1B1 inhibitors. 1
Strong OATP1B1 Inhibitors
The FDA drug label and AGA guidelines specifically identify that eluxadoline requires dose reduction when co-administered with OATP1B1 inhibitors, though the specific drugs are not exhaustively listed in the guidelines 1. However, based on the FDA label pharmacokinetic data and research evidence, the following are clinically relevant strong OATP1B1 inhibitors:
Confirmed Strong Inhibitors Requiring Dose Adjustment:
Cyclosporine - The most potent clinically studied inhibitor. Co-administration with cyclosporine (600 mg single dose) increased eluxadoline exposure by 4.4-fold (AUC) and 6.2-fold (Cmax) 2. This represents a clinically significant drug-drug interaction requiring the 75 mg dose.
Rifamycin SV - Identified as a potent OATP1B1 inhibitor in vitro 3
Additional Strong OATP1B1 Inhibitors (Based on Research Evidence):
- Indinavir - Potent OATP1B1 inhibitor associated with hyperbilirubinemia 3
- Saquinavir - Potent OATP1B1 inhibitor 3
- Gemfibrozil - Reference drug for OATP1B1 inhibition with known clinical DDI effects 4
- Atazanavir - Antiviral with significant OATP1B1 inhibition 4
- Lopinavir - Antiviral with significant OATP1B1 inhibition 4
- Amprenavir - Antiviral with significant OATP1B1 inhibition 4
Clinical Implementation
Dosing algorithm:
- Standard dose: 100 mg twice daily
- Reduced dose (75 mg twice daily) required for:
Important Caveats
The mechanism matters: Eluxadoline is a substrate for OATP1B1 2. When OATP1B1 is inhibited, hepatic uptake of eluxadoline decreases, leading to increased systemic exposure. The cyclosporine interaction study demonstrated this clinically, with a 4.4-fold increase in AUC 2.
Common pitfall: Probenecid, an OAT3 inhibitor, only modestly increased eluxadoline exposure (35% AUC increase) 2, suggesting OAT3 plays a lesser role than OATP1B1. Do not confuse OAT inhibitors with OATP1B1 inhibitors—the dose reduction is specifically for OATP1B1 inhibitors.
Safety consideration: The 75 mg dose maintains efficacy while reducing exposure-related risks. The phase 3 trials showed very similar beneficial effects between 75 mg and 100 mg doses 1, making dose reduction a safe and effective strategy when OATP1B1 inhibitors are co-administered.